Background:
In my last post, I discussed the morphology of the breast tissue and how it further differentiates into more advanced lobule types when when become pregnant. The article that discussed this postulated that this differentiation confers resistance to breast cancer mutations because there are less basic epithelial cells in the more complex breast tissue, which means they are less likely to be taken over and grow out of control when faced with mutagens (Russo, 2001). This is one hypothesis for why parous woman, women who have carried out a full pregnancy, have decreased rates of breast cancer. However, this article never gave any proof for what changes occur in the more complex lob 2-4 tissue, which makes it hard to fully accept this theory.
A Molecular Approach:
Researchers Wang and Zhao at Harvard have begun to investigate claims made my many cancer investigators that the pregnancy hormones, estrogen and progesterone, actually impact gene products and work to up or down regulate proteins in breast tissue. It was shown in an article by M.R. Ginger that the increase in estrogen and progesterone in pregnant women actually up regulates many genes, one of which being my gene of focus, RbAp46, which is a Retinoblastoma suppressor associated protein.
Wang and Zhao published an article, which focuses solely on characterizing the RbAp46 protein and how it impacts the cell when it is over expressed, as it is in pregnant women. The did this by utilizing a breast cancer line, MCF10AT3B, in a study with nude mice. When they injected this into the mice, they all developed lesions of invasive carcinoma within weeks (CMV = control). They then transfected these cancerous cells with an RbAp46 vector so that the protein of interest would be over expressed, and let the cells grow for 30 days. As shown below, 0 % of the rats who were expressing the protein had lesions, whereas 53 % of the control rats developed lesions.
(Wang, Zhao, 2003)
Molecular Analysis:
Wang and Zhao also characterized what effect the RbAp46 protein had on other proteins in the cell by looking at the levels of expressions of GADD45 on a Western Blot, as well as Northern Blot. GADD45, growth arrest and DNA damage inducible-45, is a protein that is known to regulate DNA repair, apoptosis when the cell is stressed, and cell cycle control. It essentially works as a tumor suppressor and as shown in the Western Blot below, is up regulated by the expression of the RbAp46 protein. In fact, the presence of RbAp46 does an even better job of activating this cell cycle regulator than normal DNA damaging agents like MMS (methyl methanesulfonate). The increase in RbAp46 leads to an increase of GADD45, which in turn makes the cell a better defender against damaging agents that can lead to cancer. It should be noted that RbAp46 has also been shown to be involved in histone deacetylation, which regulates transcription and prevents mutated genes from being produced.
(Wang, Zhao, 2003)
Discussion:
From the research I have done, there seems to be 2 differing theories on why pregnancy confers a resistance to breast cancer. One is the morphological pattern making cells less susceptible to mutations. The second being the molecular up regulation and down regulation of various gene products in breast tissue, which in turn activate the necessary proteins for cell regulation and death. I am proposing that both theories have some validity to them and can be used in conjunction with one another. As the breast tissue differentiates into a more complex lobule type, the signature cell receptor types could potentially change, which is why the elevated estrogen and progesterone impacts the tissue in a more protective way, increasing the level of tumor suppressor proteins and solidifying cell cycle control mechanisms via RbAp46, among other proteins not explicitly discussed here. With this theory, the increased differentiation of the breast lobules is done to ensure that the hormones of pregnancy will have the appropriate effect, thereby reducing the risk of gaining a mutation that could lead to breast cancer in pregnant women. If this connection can be established, this could open a new door in breast cancer treatment, allowing woman who don't have these up regulated protective proteins to be supplied with them in some way.
Sources:
Ginger, M. R.. "Persistent Changes in Gene Expression Induced by Estrogen and Progesterone in the Rat Mammary Gland." Molecular Endocrinology: 1993-2009. Web. 6 May 2014.
Wang, Zhao-Yi. "Overexpression of RbAp46 facilitates stress-induced apoptosis and suppresses tumorigenicity of neoplastigenic breast epithelial cells." International Journal of Cancer: 762-768. 2003. Web. 6 May 2014.
