By: Sameen Siddiqui, PharmD Candidate c/o 2025, Madelyn Lombardo, PharmD Candidate c/o 2027, and Gabriella Lamantea, PharmD Candidate c/o 2027

Breast cancer, besides skin cancer, is the most common cancer detected in women and one of the most common cancers linked to female mortality.¹ Due to the silent rapidity of the disease, breast cancer can be difficult to catch early on. Breast cancer can be diagnosed via screening, biopsy, or self-discovery of lumps on the breast. Metastasis, the spread of cancerous cells from a point of origin to other areas of the body, plays a significant role in a patient’s prognosis. When it comes to breast cancer, bone is the most common mode of metastasis because it provides a viable environment for tumor cell growth. In later stages of the disease, metastasis induces bone deterioration via osteoclast stimulation. The highly vascularized nature of bone marrow allows for tumor cells in circulation to gain access within the marrow.² Upon their arrival, breast cancer cells rearrange these vessels in a disorderly manner, contorting and scrambling them. It is here that dormant cells are found to reside. Dormant cancer cells are typically found in secondary organs where they remain until a signal is released which activates cancer growth and metastasis. Interestingly, emotional states are involved with metastasis as well. Factors such as stress, trauma and depression were shown to alter marrow tissue and stimulate metastasis. Constant activation of the sympathetic nervous system by these emotional states has been shown in studies to increase osteoclast activity and promote the spread of osteolytic lesions, a characteristic sign of metastatic breast cancer.²

The term “tumor microenvironment” (TME) refers to the physical surroundings of a tumor which involves components like immune cells, cytokines, and pH levels. When examining the complex territory, three levels exist: the local, regional, and metastatic. The local level refers to the environment within the tumor itself, while the regional microenvironment is the leading site of cancerous growth. In the case of breast cancer, the regional level is the breast. Finally, the metastatic level refers to any secondary cancerous growths in other distant body niches.³ Within these levels are several kinds of cells, each contributing to the tumor in some way. Cancer-associated fibroblasts (CAFs) comprise the majority of cells in cancerous breast stroma and play a significant role in tumor development and cell invasion. Through extensive study, we have come to understand that CAFs contain specific mRNA that is unlike that of fibroblasts residing in normal non-cancerous breast tissue.⁴ The origins of cancer-associated fibroblasts are not entirely understood, though some postulate that women with certain single nucleotide polymorphisms have fibroblasts with increased expression of a protein called MMP3, which promotes cancer cell invasion.⁴

Tumor-associated macrophages (TAMs) are another population of cells that make up a large percentage of the cancerous environment. They can be divided into two classes: M1 and M2. M2 macrophages, whose usual functions involve mending wounds and remodeling tissue, are the ones that are primarily involved with the survival and proliferation of cancer cells via cytokine secretion. Similar to the macrophages are tumor infiltrating lymphocytes, another cell type consisting of different classes. Of these classes, our main focus is on regulatory T cells. These cells work against the body’s autoimmune responses.

Regulatory T cells normally halt autoimmune reactions, though when residing in the TME, block anti-tumor responses. They also have a role in cancer progression by producing high amounts of a protein called receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL can activate breast cancer cells with RANK receptors, therefore leading to metastasis.⁴ Higher amounts of RANKL are associated with increased osteoclast activity as well; this increased osteoclast activity may lead to the advancement of tumor growth in bones, which is a frequent site of metastasis for breast cancer.²

Within tumor-associated stroma are immature dendritic cells whose normal function is marred. Due to incomplete functionality, these cells cannot act on their anti-tumor capabilities; in fact, they even work against the body to promote tumor development. Finally, the extracellularmatrix, which is usually a stable and supportive environment, is observed to be quite the opposite in cancerous tissue. The rigid stroma of cancerous extracellular matrix forms the characteristic lumps of breast cancer. An enzyme known as lysyl oxidase causes this rigidity to occur and serves as a marker of cancer progression. Cancerous extracellular matrix may also interfere with regular immune function via stunting regulatory T cell growth and disrupting their abilities.⁴

Breast cancer has many options for treatment depending on how far the cancer has spread based on medical scans and decisions made by patients. Presently, there exist three treatment options utilizing breast TME as a target: aromatase inhibitors, human epidermal growth factor receptor 2 (HER2) inhibitors, and angiogenesis inhibitors.⁴ Aromatase and HER2 inhibitors work against certain aspects in the stroma. For example, aromatase inhibitors such as anastrozole, letrozole, and exemestane block the aromatase enzyme which prevents the conversion of androgens to estrogen, ultimately decreasing tumor growth in hormone receptor-positive breast cancer patients.⁵ HER2 inhibitors (i.e., trastuzumab and pertuzumab) are specific to breast cancer patients whose tumor growth is due to overexpression of human epidermal growth factor 2 HER2 receptor-positive breast cancer. These drugs function by blocking HER2 signaling triggered by stromal growth factors in breast cancer patients. Vascular endothelial growth factor (VEGF) inhibitors such as bevacizumab is a cytokine produced by TAMs that prevent the growth of new blood vessels. Dendritic cells show some promise in being a possible target for breast cancer treatment as well. By promoting the development of immature dendritic cells in the tumor-associated stroma, this method may increase their anti-tumor activity and therefore decrease proliferation of the malignancy.⁴

TME is a topic undergoing continuous research. In order to help patients with cancer, investigators must understand how the various cells of TMEs communicate with one another. Once the communication within these signaling networks is prevented, tumor growth can be suppressed.⁶ Present-day technology lends itself to studying TMEs; for example, the development of multi-omics technologies that combine methods such as transcriptome and proteome. This provides an advantage to scientists when comprehending the cancer because it provides the diverse makeup of the tumor in the TME, resulting in a better understanding of the cancer stage and developing a more precise and accurate treatment. In addition, TMEs aim to have better therapeutic advantages than cancer treatments like immunotherapy and radiation therapy. In TME, cells that are non-tumor are more exposed and stable compared to tumor cells. This shows a therapeutic advantage due to their instability because cancer cells are more inclined to drug resistance.⁷

In conclusion, breast cancer is a major topic in women’s health and a disease state that is important to regularly screen for. Metastasis, the spread of cancerous cells, is expected mainly in the bone and can happen when a patient experiences major emotional imbalances such as high stress as this can cause an anatomical change to the marrow tissue. TME and its components play a unique role in the development and metastasis of cancer. Each cell involved in the cancerous environment contributes in their own way to tumor development, with cancer-associated fibroblasts being the largest population of these cells. Others include the M2 class of tumor associated macrophages which facilitate cancer cell proliferation, a kind of tumor infiltrating lymphocyte known as regulatory T cells which suppress autoimmune responses and increase osteoclast activity, and immature dendritic cells which promote tumor development. Today, TME is still being researched to help patients with cancer. Technology, such as multi-omics, has improved significantly over the years, which can help scientists figure out more ways to develop treatments for patients.

References

1. ‌What is breast cancer? Centers for Disease Control and Prevention. Last Reviewed July 25, 2023. https://www.cdc.gov/cancer/breast/basic_info/what-is-breast-cancer.htm
2. Zarrer J, Haider MT, Smit DJ, Taipaleenmäki H. Pathological Crosstalk between Metastatic Breast Cancer Cells and the Bone Microenvironment. Biomolecules. 2020;10(2):337. Published 2020 Feb 19. doi:10.3390/biom10020337
3. Li JJ, Tsang JY, Tse GM. Tumor Microenvironment in Breast Cancer-Updates on Therapeutic Implications and Pathologic Assessment. Cancers (Basel). 2021;13(16):4233. Published 2021 Aug 23. doi:10.3390/cancers13164233
4. Soysal SD, Tzankov A, Muenst SE. Role of the Tumor Microenvironment in Breast Cancer. Pathobiology. 2015;82(3-4):142-152. doi:10.1159/000430499
5. Goldfarb SB, Hudis C, Dickler MN. Bevacizumab in metastatic breast cancer: when may it be used?. Ther Adv Med Oncol. 2011;3(2):85-93. doi:10.1177/1758834010397627
6. Shi Y, Zhang Q, Mei J, Liu J. Editorial: Multi-omics analysis in tumor microenvironment and tumor heterogeneity. Frontiers in Genetics. 2023;14. doi:https://doi.org/10.3389/fgene.2023.1271295
7. Xiao Y, Yu D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol Ther. 2021;221:107753. doi:10.1016/j.pharmthera.2020.107753

Published by Rho Chi Post